Rhabdomyolysis

Rhabdomyolysis Classification and external resources
Model of helical domains in myoglobin, the protein linked to kidney damage in rhabdomyolysis.
ICD-10	M62.8, T79.6
ICD-9	728.88
DiseasesDB	11472
MedlinePlus	000473
eMedicine	ped/2003  emerg/508
MeSH	D012206

Rhabdomyolysis is the rapid breakdown (lysis) of skeletal muscle tissue (rhabdomyo) due to injury to muscle tissue. The muscle damage may be caused by physical (e.g. crush injury), chemical, or biological factors. The destruction of the muscle leads to the release of the breakdown products of damaged muscle cells into the bloodstream; some of these, such as myoglobin, are harmful to the kidney and may lead to acute kidney failure. Treatment is with intravenous fluids, and dialysis or hemofiltration if necessary.^[1]

Rhabdomyolysis and its complications are major problems in people who are injured in disasters such as earthquakes and bombing. The disease and its mechanisms were first elucidated in the Blitz of London in 1941.^[2]

Signs and symptoms

Most cases of rhabdomyolysis develop as a result of muscle injury or strain, or other external causes (such as medication or intoxication). However, the cause is not always directly evident. Pain, tenderness, weakness and edema (swelling) of the affected muscles may be present. If the swelling is very rapid (such as after being released from a collapsed building), low blood pressure and shock may be present due to depletion of fluid from the bloodstream. Other symptoms are nonspecific and result either from the consequences of the breakdown in muscle tissue, or from the condition that caused the muscle breakdown.^[1][3]

Swelling of the damaged muscle occasionally leads to compartment syndrome, the compression by swollen muscle of surrounding tissues in the same fascial compartment (such as nerves and blood vessels), leading to damage or loss of function in the part of the body supplied by these structures. Symptoms of this complication include decreased blood supply, decrease in sensation, or pain in the affected limb.^[3]

Release of the components of muscle tissue into the bloodstream leads to disturbances in electrolytes, causing nausea, vomiting, confusion, coma and cardiac arrhythmias (abnormal heart rate and rhythm). Furthermore, damage to the kidneys may lead to dark (tea-colored) urine or a marked decrease (oliguria) or absence (anuria) of urine production, usually about 12–24 hours after the initial muscle damage. Finally, disruptions in blood clotting may lead to the development of a state called disseminated intravascular coagulation.^[1][3]

Causes

Alfred P. Murrah Federal Building after a 1995 bombing that injured or killed more than 1,000 people. Collapsing buildings can cause crush injuries that trigger rhabdomyolysis.

Anything that destroys muscle tissue can cause rhabdomyolysis. The causes of rhabdomyolysis can be classified as either physical or non-physical. Physical rhabdomyolysis is in some situations confined to a particular area of the body, while rhabdomyolysis due to other causes tends to affect all muscles simultaneously.^[1]

Physical causes

Recognized physical causes for rhabdomyolysis are:^[1]

• Traumatic compression of muscles: crush syndrome (e.g. in earthquakes), car accident, confinement in a fixed position (e.g. after a stroke, due to drunkenness or in prolonged surgery), physical torture or abuse
• Obstruction of blood supply to muscles: arterial thrombosis (blood clots forming locally) or embolism (clots or other debris from elsewhere in the body), clamping of an artery during surgery, generally reduced blood supply in shock or sepsis (due to any cause)
• Excessive muscle strain or activity: extreme physical exercise (particularly when poorly hydrated), delirium tremens (alcohol withdrawal), tetanus, prolonged seizures or status epilepticus
• Electrical: lightning, high-voltage electric shock, including electroshock weapon injuries^[4]

Non-physical causes

Non-physical causes reported to cause rhabdomyolysis include:^[1]

• Disorders of muscle energy supply (usually hereditary enzyme problems): carnitine deficiency, CPT type I or type II deficiency, McArdle's disease, various defects in the mitochondrial respiratory chain, phosphofructokinase deficiency, VLCAD deficiency^[5]
• Poisons such as heavy metals and venom from insects or snakes
• Foodborne toxins, e.g. coniine from quail that have consumed hemlock (coturnism),^[6] Tricholoma equestre mushrooms in France and Poland,^[7] and an unidentified toxin in fish (Haff disease)^[8]
• Drugs of abuse,^[9] including: ethanol,^[10] methamphetamines,^[11] cocaine,^[12] heroin,^[13] phencyclidine (PCP),^[14] ketamine,^[15] 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy)^[16][17]
• Medications:
  • statins, especially when prescribed in combinations with fibrates. Cerivastatin (Baycol) was withdrawn in 2001 after numerous reports of rhabdomyolysis. Other statins have a small risk of 0.44 cases per 10,000 patients annually, which increases to 5.98 if a fibrate is added.^[18] However, other studies detected no increased risk from statins.^[19]
  • anti-psychotic medications may cause neuroleptic malignant syndrome, which can cause severe muscle rigidity, with rhabdomyolysis and hyperpyrexia
  • neuromuscular blocking agents, used in anasthesia may cause malignant hyperthermia, also associated with rhabdomyolysis
  • medications that interfere with potassium levels (e.g. diuretics)
• Infections: Coxsackie virus, Plasmodium falciparum (malaria), herpes viruses, Legionella pneumophila, Salmonella and Francisella tularensis (tularemia)
• Electrolyte and metabolic disturbances: increased plasma osmolality, hyper- and hyponatremia (elevated or reduced blood sodium levels), hypokalemia (low potassium levels), hypocalcemia (low calcium levels), hypophosphatemia (low phosphate levels), ketoacidosis (e.g. in diabetes) or hypothyroidism (abnormally low thyroid function)
• Autoimmune muscle damage: polymyositis, dermatomyositis

Diagnosis

Creatine kinase (M chain), the muscle energy enzyme elevated in the blood of patients with rhabdomyolysis.

The diagnosis may be suspected in anyone who has suffered a trauma, crush injury or prolonged immobilization, but it may also be identified at a later stage due to deteriorating kidney function (abnormally raised or increasing creatinine and urea levels, falling urine output) or typical pink-red discoloration of the urine. High potassium levels (hyperkalemia) tend to be a feature. Low calcium levels may be present in the initial stage, and about a quarter of patients have abnormal liver function tests due to liver damage.^[1] Dipstick analysis of urine may reveal a positive result for "blood" in the absence of red blood cells on microscopy, as the reagent reacts with myoglobin.^[2] Cardiac troponin levels (normally used to diagnose heart damage) are increased in half of all cases, but not associated with other evidence of heart damage in at least a third of those cases.^[20]

The most reliable test in the diagnosis of rhabdomyolysis is the level of creatine kinase (CK) in the blood. This enzyme is released by damaged muscle, and levels above 5 times the upper limit of normal (ULN) indicate rhabdomyolysis. Depending on the extent of the rhabdomyolysis, levels up to 100,000 units are not unusual.^[2] Initial and peak CK levels have a linear relationship with the risk of acute renal failure: the higher the CK, the more likely it is that kidney damage will occur.^[21] CK levels rise after 12 hours of the initial damage, remain elevated for 1–3 days and then fall gradually. Myoglobin has a short half-life, and is therefore less useful as a diagnostic test in the later stages.^[1]

Compartment syndrome is a clinical diagnosis (i.e. no tests conclusively prove its presence or absence), but direct measurement of the pressure in a fascial compartment may be used to assess its severity. Values of 30–50 mmHg (4–6.5 kPa) indicate severe compartment syndrome and possible need for fasciotomy, which is an incision to relieve increased pressure.^[2]

Pathophysiology

Damage to skeletal muscle may take various forms. Crush injuries damage muscle cells directly, as well as impairing the blood supply; other causes may damage muscle cells by interfering with their metabolism. The muscle tissue rapidly fills with fluid from the bloodstream, as well as sodium and chloride. The swelling itself may lead to destruction of muscle cells, but those cells that survive react by pumping sodium out of the cells in exchange for calcium (through the sodium-calcium exchanger). The accumulation of calcium in the sarcoplasmic reticulum leads to continuous muscle contraction and depletion of ATP, the main carrier of energy in the cell. Calcium also stimulates the enzyme phospholipase A2, which damages the mitochondrion, causing the production of reactive oxygen species.^[22] In addition, neutrophil granulocytes (the most abundant white blood cells) enter the muscle tissue, producing an inflammatory reaction and releasing even more reactive oxygen species.^[2]

The swollen and inflamed muscle may directly compress structures in the same fascial compartment, causing compartment syndrome. The swelling may also further compromise blood supply into the area. Finally, destroyed muscle cells release potassium, phosphate, myoglobin (a heme and therefore iron-containing protein), creatine kinase (an enzyme) and uric acid (a breakdown product of purines from DNA) into the blood. Activation of the coagulation system may precipitate diffuse intravascular coagulation.^[2] High potassium levels (hyperkalemia) may lead to potentially fatal disruptions in heart rhythm. Phosphate precipitates with calcium from the circulation, leading to hypocalcemia (low calcium levels).^[2]

Various consequences of muscle swelling and breakdown together may cause renal failure. The swelling of large areas of muscle tissue leads to depletion of fluid from the circulation, causing relative lack of blood flow to the kidney. Uric acid may precipitate in the tubules, causing obstruction. Finally, the most important problem is the accumulation of myoglobin in the tubules.^[2] Myoglobinuria (the appearance of myoglobin in the urine) occurs when the levels in plasma exceed 1.5 mg/dl.^[1] As the kidneys reabsorb more water from the filtrate, myoglobin forms casts that obstruct the normal flow of fluid through the nephron; the condition is worsened by high levels of uric acid and acidification of the filtrate. Iron released from the myoglobin generates reactive oxygen species, damaging the kidney cells. Acute tubular necrosis (destruction of the cells of tubules) occurs, preventing the kidney from performing its normal excretory functions (hence the fall in glomerular filtration rate), electrolyte regulation (hence worsening potassium levels) and hormone production (hence decreased vitamin D processing, further worsening the low calcium levels).^[2]

Treatment

Fluid therapy

The main goal of treatment is to treat shock and preserve kidney function. Initially this is done through the administration of generous amounts of intravenous fluids, usually saline (0.9% weight per volume sodium chloride solution). In victims of crush syndrome (e.g. in earthquakes), it is recommended to start this even before the casualties are extracted from collapsed structures. This will ensure sufficient circulating volume to deal with the muscle cell swelling (which typically commences when blood supply is restored), and to prevent the deposition of myoglobin in the kidneys. Amounts of 6 to 12 liters over 24 hours are recommended.^[2]

While many sources recommend mannitol, which acts by osmosis to ensure urine production and may prevent heme deposition in the kidney, there are no studies directly demonstrating its benefit. Similarly, the addition of bicarbonate to the fluids is intended to improve acidosis (high acid level of the blood) and thereby prevent cast formation in the kidneys, but there is limited evidence that it has benefits above saline alone. Furosemide, a loop diuretic, is often used to ensure sufficient urine production.^[1][2]

Electrolytes

In the initial stages, electrolyte levels are often abnormal and require correction. Calcium levels initially tend to be low, but as the patient's condition improves calcium is released from where it has precipitated with phosphate, and vitamin D production resumes, leading to hypercalcemia (abnormally high calcium levels). This "overshoot" occurs in 20–30% of those people who have developed kidney failure.^[1]

Acute renal failure

A hemodialysis machine

If kidney dysfunction (acute renal failure, ARF) develops (usually 1–2 days after the initial muscle trauma), renal replacement therapy (RRT) may be required. This may take the form of hemodialysis or hemofiltration. Certain types of peritoneal dialysis are also effective in removing the high levels of toxic solutes that can accumulate in rhabdomyolytic renal failure, and may be the only available option in some Third World settings.^[23]

RRT removes excess potassium, acid and phosphate that accumulates when the kidneys are unable to function normally and is required until kidney function is regained.^[1]

Other complications

Main articles: compartment syndrome and diffuse intravascular coagulation

Compartment syndrome and diffuse intravascular coagulation, as well as any other complications of rhabdomyolysis, are treated in the same way as in other situations in which they may arise.^[1]

Prognosis

The prognosis depends significantly on the underlying cause and whether any complications occur. Rhabdomyolysis patients who experience acute renal failure (ARF) may have a mortality rate as high as 20%.^[1]

Epidemiology

Rhabdomyolysis is a relatively rare condition in everyday life. The rate of rhabdomyolysis in the general population is difficult to establish with certainty, but was estimated by one U.S. study to be about 2 cases per 10,000 person-years.^[19] Another study found 26,000 cases per year in the U.S.^[3]

Up to 85% of patients with major traumatic injuries will experience some degree of rhabdomyolysis.^[1] Approximately 15% of patients with rhabdomyolysis will experience acute renal failure as a complication, although rates vary between studies.^[3] Rhabdomyolysis is a significant cause of renal failure, and may account for as much as a quarter of the cases of this condition.^[1]

Crush injury is common in major disasters, but especially so in earthquakes. The 1988 Spitak earthquake led to the recognition that many initial survivors of major earthquakes later succumb to rhabdomyolysis. In 1995 the International Society of Nephrology, a worldwide body of kidney experts, established a group named the Renal Disaster Relief Task Force to assist in similar emergencies. Its volunteer doctors and nurses assisted for the first time in the 1999 İzmit earthquake in Turkey, where 462 patients received dialysis, with positive results. Treatment units are generally established outside the immediate disaster area, as aftershocks could potentially injure or kill staff and make equipment unusable.^[1]

History

The Bible may contain an early account of rhabdomyolysis. In Numbers 11:31–33, the Pentateuch relates that the Jews demanded wholesome food while traveling in the desert; God sent quail in response to the complaints, and people ate large quantities of quail meat. A plague then broke out, killing numerous people. Rhabdomyolysis after consuming quail was described in more recent times, and called "coturnism" (after Coturnix, the main quail genus).^[24] It is known that migrating quail consume large amounts of hemlock, which contains the poisonous alkaloid coniine, and a 1991 study showed that coniine may cause rhabdomyolysis.^[6][1]

In modern times, early reports from the 1908 Messina earthquake and World War I on renal failure after injury were followed by studies by E. Bywaters and D. Beall on four victims of The Blitz in 1941. A role for myoglobin was suspected.^[25] Myoglobin was demonstrated in the urine of victims by spectroscopy,^[26] and it was noted that the kidneys of victims resembled those of patients who had received an incorrectly matched blood transfusion (an observation made in 1925), with the received blood being destroyed by the immune system (hemolysis) and hemoglobin accumulating in the kidney.^[27] In 1944 Bywaters demonstrated experimentally that the renal failure was mainly caused by myoglobin.^[2][28]

References